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Peripheral Catecholamine Levels and the Symptoms of Anxiety:Studies in Patients With and Without Pheochromocytoma

MONICA N. STARKMAN, MD, MS, OLIVER G. CAMERON, MD, PHD,RANDOLPH M. NESSE, MD, AND THOMAS ZELNIK, MD

We studied the correlation of plasma and urinary epinephrine (E) and norepinephrine (NE)levels with anxiety symptoms in three patient groups: 1) pheochromocytoma (PH+) (n = 17);2) hypertensives with elevated catecholamine levels shown not to have a PH (PH—) (n = 25);and 3) patients with panic disorder (PD) (n = 23). Structured interviews and four self-ratedanxiety scales were used, the SCL-90R Anxiety and Phobic Anxiety scales, and the SpielbergerState/Trait Anxiety Inventories. The SCL-90R Somatization scale (which measures 12 somaticsymptoms) was also utilized. None of the PH+ patients met DSM-III criteria for PD. Two metcriteria for generalized anxiety disorder (GAD). Of the PH— patients, two had PD, two hadGAD. and three had both. Urinary and plasma E did not show significant positive correlationswith any of the four anxiety scales in any of the three patient groups. In both the PH+ andPH— groups, E was significantly correlated with the SCL-90R Somatization scale. NE was notsignificantly correlated with any of the four anxiety scales in the PH+ group. In contrast, inthe PH— group, plasma NE was significantly correlated with anxiety on all anxiety scales (r =+0.55 to +0.77, p < 0.05). Furthermore, in the PH- group, plasma NE was significantlycorrelated with those items of the SCL-90R Anxiety scale measuring the cognitive rather thanthe noncognitive symptoms of anxiety. In the PD group as well, plasma NE showed a significantcorrelation with the SCL-90R Anxiety Scale (r = +0.67, p < 0.05). Taken together, ourobservations suggest that: 1) the effects of catecholamines in the periphery derived from asource independent of nervous system control (such as a PH) are not sufficient to elicit ananxiety disorder meeting DSM-III criteria; and 2) in patients without an autonomous source ofperipheral catecholamines, NE in the periphery results from sympathetic nervous systemactivation and probably reflects, rather than causes, anxiety.

INTRODUCTION

Recent refinements in the classificationof anxiety disorders and the availabilityof more efficacious pharmacologic treat-ments have renewed interest in thepathophysiology of anxiety. In this regard,

From the University of Michigan Medical School,Ann Arbor. Michigan.

Address reprint requests to: Monica N. Starkman,M.D., M.S., Consultation/Liaison Psychiatry, Uni-versity of Michigan Hospitals, 1500 E. Medical Cen-ter Drive. Ann Arbor, MI 48109-0840.

Received May 27,1988; revision received October24, 1989.

one area of both historical and currentinterest is the role played by peripheralas well as central catecholamines.

Three lines of investigation bear on thisquestion. The first addresses catechol-amine elevation in response to psychoso-cial stimuli. Various psychosocial stimuliare known to influence catecholaminelevels, but the exact relationship betweenthe kinds of stimuli and the patterns ofresponse remains uncertain. Threat haslong been known to induce catechol-amine secretion in a variety of species (1).Subsequent research has shown that awide variety of noxious physical or psy-chological stimuli release catecholamines(2, 3). Pleasant arousal is also associated

Psychosomatic Medicine 52:129-142 (1990) 129

0033-3174/90/5205-0129J02 00/0Copyright ffl 1990 by the American Psychoso

M. N. STARKMAN et al.

with elevated catecholamine levels (2).More recently, anxiety induced by in vivoflooding in phobic patients was found tostimulate catecholamine excretion inde-pendent of pain or muscular activity (4).Some studies of catecholamine secretionsuggested that epinephrine (E) release wasassociated with fear and anxiety and nor-epinephrine (NE) with aggression (5). Ma-son (6) proposed that E was increased insituations characterized by novelty anduncertainty, whereas NE rose in unpleas-ant but familiar conditions. Levi (7] re-ported that either positive or negativeemotional arousal produces rises in bothmean E and NE levels. In phobic patientsundergoing flooding therapy, NE showeda more consistent elevation, whereas E,when elevated, showed a greater magni-tude of increase (4). Although patientswith panic disorder were thought to showMHPG elevation during situational panicattacks (8), it now appears that panic itselfhas little effect on plasma MHPG levels(9), and that venous plasma E is un-changed, whereas plasma NE is eitherunchanged or minimally elevated duringspontaneous panic attacks [10). In sum-mary, catecholamines have been shownto change in response to psychologicalstimuli, but no simple principle explainsall of the relationships observed.

The second line of investigation ad-dresses symptoms that result from theadministration of catecholamines or "cat-echol-like" compounds. Isoproterenol in-duces physical symptoms in normal sub-jects, including palpitations, dyspnea, andsweating (11). In normal subjects, theemotional reaction to intramuscular in-jection of E is largely determined by theassociated social setting and expectations(12); in a neutral setting, both E and NEhave similar effects, neither inducing spe-

cific or strong emotions, although theirphysical effects simulate a state of arousal(2). In patients with panic disorder, iso-proterenol may precipitate anxiety at-tacks (13), even though these patientshave /3-adrenergic receptors that are lesssensitive than those of normal subjects(14). Thus, catecholamines change psy-chological states and psychological eventschange catecholamine levels; the inter-actions are complex.

The third line of investigation dealswith resting levels of catecholamines inpsychiatric patients and normal subjects.In some studies, while patients with panicdisorder had elevated resting plasma lev-els of E, NE, and MHPG (14, 15), anxietyratings were not correlated with the cate-cholamine levels (15). Compared to nor-mal subjects, some panic disorder patientsshow elevated levels of nighttime urinaryNE and, to a lesser extent, E (16), and tendto have elevated urinary excretion ofMHPG (17). As for patients with general-ized anxiety disorder, they may or maynot have elevated plasma catecholaminelevels (18). In patients with depressivedisorder, plasma catecholamine levelscorrelate better with anxiety ratings thanwith depression ratings (19), and anxiousdepressives in particular also have ele-vated cerebrospinal fluid (CSF) NE levels(20). In normal subjects, one study re-ported high trait anxiety as measured bythe Spielberger Trait Anxiety Scale to bepositively correlated with higher plasmaMHPG elevations (21), but in anotherstudy, plasma MHPG correlated nega-tively with trait anxiety (22). However,CSF MHPG correlated positively withstate anxiety just prior to lumbar punc-ture (22). All in all, while resting cate-cholamines appear to be somewhat ele-vated in patients with panic disorder and

130 Psychosomatic Medicine 52:129-142 (1990)

PERIPHERAL CATECHOLAMINE LEVELS AND ANXIETY

are possibly elevated in patients withmore generalized anxiety, stronger gen-eralizations are not yet warranted.

Thus, despite previous and current re-search, the question of whether periph-eral E and NE play an etiologic role inproducing anxiety, as suggested by theJames-Lang hypothesis, or are simply con-comitants of the state of arousal, has stillnot been satisfactorily answered.

In order to explore further the relation-ship between peripheral catecholaminelevels and anxiety, we studied the corre-lation of E and NE with anxiety ratings inthree patient groups with special featuresthat bear on this question. One group ofpatients had pheochromocytomas, tumorsof adrenal medullary cells that releasehigh levels of catecholamines into the cir-culation. They do so autonomously andnot through autonomic nervous systemstimulation, responding instead to suchstimuli as change in position. Since pe-ripheral catecholamines do not appear tocross the blood-brain barrier in physiolog-ically significant amounts (23-25], thesepatients provide an opportunity to studythe effect of autonomously secreted ele-vated peripheral catecholamine levels onsymptoms of anxiety. The second groupof subjects were patients with hyperten-sion and/or elevated catecholaminelevels, who were initially suspected ofhaving a pheochromocytoma but weresubsequently shown not to have such atumor. The elevated peripheral catechol-amines in these patients result not froman autonomous tumor but from sympa-thetic nervous system activity and sym-pathetic stimulation of the adrenal me-dulla, presumably under the complexcontrol of the central nervous system.This group was of interest because thehigh mean catecholamine levels and wide

variation of values among individuals inthe group can provide information regard-ing the association of anxiety symptomsand elevated catecholamine levels whichresult from sympathetic nervous systemactivity.

We studied one additional group of pa-tients for comparison. This third groupconsisted of patients meeting DSM-III cri-teria for panic disorder or for agoraphobiawith panic attacks. This group permittedassessment of whether NE and/or E levelsare correlated with the somatic and/orcognitive symptoms of anxiety in patientswith anxiety disorders who characteris-tically have mildly rather than markedlyelevated catecholamine levels.

We report here that there were no sig-nificant correlations of anxiety symptomswith peripheral NE or E levels in thepatients with pheochromocytoma. In con-trast, in the patients without a pheochro-mocytoma and in the panic disorder pa-tients, anxiety correlated significantlywith plasma NE but not with plasma E.

METHODS

Subjects with Actual or SuspectedPheochromocytomaSubjects were recruited through the University

of Michigan Medical Center Nuclear Medicine Unit,an international referral center which provided aunique opportunity to study patients with suspectedpheochromocytoma. The presence of pheochromo-cytoma was determined by scintigraphic imagingafter the injection of [13lI]mefa-iodobenzyl guanidine([131I]MIBG). This compound resembles NE in molec-ular structure and is thought to enter the adrenergictissue of pheochromocytomas by the same uptakemechanism (26).

During a 9-month period, all patients referred foran MIBG scan because of suspected pheochromocy-toma were evaluated. Seventeen patients were sub-sequently determined to have a pheochromocytoma.



This diagnosis was established by: a) plasma andurine catecholamine and urine catecholamine me-tabolite levels; b) abnormal scintigraphic imageswith [131I]MIBC, which is highly specific for pheo-chromocytoma; and c) the histologic appearance oftumor tissue, when available. Fourteen patientswere Caucasian, 2 were Afro-American, and 1 wasAmerican Indian. Thirteen were male and 4 werefemale. Their mean age was 42.5, with a range of 18to 68 years. Fourteen of these pheochromocytoma-positive patients had sustained persistent hyperten-sion, 2 had paroxysmal hypertension, and 1 wasnormotensive. Eleven of these patients were receiv-ing a-adrenergic blocking agents, and 8 were receiv-ing /J-adrenergic blocking agents. While we wouldhave preferred to study patients drug-free, most hadsignificant hypertension, and antihypertensive med-ication could not be withdrawn solely for purposesof this study. Elevated blood pressure and heart ratein most of these patients, however, indicated contin-uing effects of the excessive catecholamine levelsdespite pharmacotherapy. One patient was receivinga benzodiazepine. No patient was receiving antide-pressant or antipsychotic medication.

Twenty-five patients who had an MIBG scan werefound not to have a pheochromocytoma. Twenty-three of these patients were Caucasian, 2 were Afro-American. Fifteen were male and 10 were female.Their mean age was 40, with a range of 21 to 61years. Twenty of these 25 pheochromocytoma-neg-ative patients had hypertension, 12 persistent and 8paroxysmal. At evaluation. 6 patients were receivinga-adrenergic blocking agents, and 8 were on /3-ad-renergic blocking agents. Two of 25 patients werereceiving benzodiazepine medication. None was re-ceiving antidepressant medication, and 1 was receiv-ing antipsychotic medication.

Subjects with Panic DisorderTwenty-three patients with panic disorder or ago-

raphobia with panic attacks were studied. Thesepatients had requested treatment at the Universityof Michigan Anxiety Disorders Program, and werethe same individuals reported on in prior publica-tions (14, 27). Diagnoses were established accordingto DSM-III criteria (28) after a clinical examinationby a psychiatrist experienced in diagnosing anxietydisorders (O.G.C., R.M.N.). All subjects were Cau-casian. Five were male, and 18 were female. Theirmean age was 32, with a range of 18 to 53. Allsubjects were physically healthy (except for mitral

valve prolapse in 7), were normotensive, and nottaking any medication. All but 2 subjects had beenmedication-free for a month or more. One patienthad taken diazepam and trifluoperazine. and an-other had taken diazepam and naldolol until twoweeks before the study. Fourteen of these 23 patientsprovided both plasma and urine specimens for cate-cholamine level studies, while the remaining 9 pro-vided urine specimens only.

Normal SubjectsIn order to obtain a comparison group for levels

of catecholamine elevation, plasma and urinary Eand NE were studied in a group of nine normalhealthy subjects. Seven were male and two female,with a mean age of 26 and a range of 20-34 years.

Informed consent was obtained from each patientand normal subject after the nature of the study wasfully explained.

Psychiatric Evaluation and Self-ratedScales

A full description of the psychiatric evaluationand self-rated scales used has been reported previ-ously (29). Patients being tested for a suspected phe-ochromocytoma were given a psychiatric evaluationduring the 3-day period of their MIBG scan protocol.The interview was designed to collect data thatwould bear on the diagnoses of panic disorder, gen-eralized anxiety disorder, and major depressive ep-isodes, as defined by the Diagnostic and StatisticalManuaJ of Mental Disorders (Third Edition) (DSM-III) (28).

The psychological and physical symptoms char-acterizing paroxysmal episodes ("attacks"), as wellas chronic symptoms, were assessed for each indi-vidual in the suspected pheochromocytoma group.A description of the first episode (prior to the initi-ation of antihypertensive medication) was obtained,as well as information about any changes in symp-tom profile over time or after the initiation of med-ication.

For all three patient groups, each subject com-pleted the Symptom Checklist-90-Revised (SCL-90R), a self-report symptom inventory designed tomeasure current psychological symptom statusrather than personality (30). The SCL-90R includesan Anxiety scale that reflects levels of somatic and



psychic anxiety, a Phobic Anxiety scale that con-tains items related to agoraphobia, and a Somatiza-tion scale that reflects distress arising from percep-tions of bodily functions. The Spielberger State/TraitAnxiety Inventory (31) was also administered toeach subject being tested for pheochromocytoma.

Psychological test scores and DSM-III diagnoseswere established before knowledge of patients'MIBG scan results or catecholamme levels.

Hormone MeasurementsPatients with suspected pheochromocytoma were

tested for plasma E and NE on the first morning oftheir evaluation prior to MIBG study. An indwellingcatheter was placed in an arm vein, and patientsrested supine for 30 min before a single blood spec-imen was drawn. Patients also collected a 12-hrovernight urine specimen at home, refrigerated thesample, and brought it with them on the morningthat blood was to be drawn. For purposes of thisanalysis, values of the 12-hr overnight urine collec-tion were multiplied by 2 to give an estimate of a24-hr value. It should be noted that these estimatesdo not reflect circadian variability (slightly greaterexcretion during the daytime).

Plasma levels of E and NE were determined by aradioenzymatic method (32). Urinary concentrationsof unconjugated NE and E were determined by themethod of von Euler and Lishajko (33). For panicdisorder patients and normal subjects, blood speci-mens were also drawn via an indwelling catheterafter patients rested supine for 20, 30, and 40 min; amean value for these three time points was calcu-lated. Urines were collected as two 12-hr specimens,and a mean value for the two specimens was usedin the data analysis. Specimens were processed asdescribed previously (14, 27).

Statistical MethodsHistograms revealed that the raw values of hor-

mone levels in plasma and urine were not normallydistributed, especially for pheochromocytoma-posi-tive patients. Natural log transformations producedmnrp nnrmal HisMhiiHnnQ anH wprp thprpfnrp ncprl

mone levels in each of the three patient groups.Because of the number of correlations studied, weelected to accept only correlation coefficients bothstatistically significant and of a magnitude of + 0.40or greater. Given the sample size and our interest inpatterns of relationships within a group and acrossgroups, rather than the statistical significance of anysingle correlation per se, we did not adjust the sig-nificance level, and accepted a 0.05 level of signifi-cance despite the fact that this may yield an over-estimate of the number of statistically significantcorrelations.

RESULTS

Mean Catecholamine Levels ofPheochromocytoma-positive,Pheochromocytoma-negative, andPanic Disorder Patients

The mean catecholamine levels (±SD)in plasma and urine for all groups areshown in Table 1. Mean levels in ninenormal subjects are also given for com-parison. As can be seen by inspection,compared to normal levels, the meancatecholamine levels were massively el-evated in the pheochromocytoma-posi-tive group, substantially elevated in thepheochromocytoma-negative group, andsomewhat elevated in the panic disordergroup.

DSM-III Diagnoses and TheirAssociation with CatecholamineLevels

Pheochromocytoma-positive patients.For the 3-week period preceding the eval-uation, 12 of the 17 pheochromocytoma-positive patients experienced at least oneparoxysmal symptom episode. Headachewas the most prominent physical symp-tom during these episodes; sweating, rest-lessness, nausea, palpitations and tachy-



TABLE 1. Epinephrine and Norepinephrine Levels in Pheochromocytoma-positive,Pheochromocytoma-negative, Panic Disorder Patients and Normal Subjects

Pheochromocytoma-positive (N = 17)Pheochromocytoma-negative (N = 25)Panic disorder (N = 23)Normal subjects (N = 9)

Plasma E(pg/ml)

950 ± 2623-105 ±28852 ±2531 ±24

Urine E(Mg/24 hr)

105 ± 19110 ± 913 ± 48 ± 3

Plasma NE(pg/ml)

2376±1778363 ± 259298 ± 85222 ± 38

Urine NE(Mg/24 hr)

432 ± 30747 ±2933 ± 81 8 ± 5

1 Values are means ± SD.

cardia, shortness of breath, and epigastricdistress also were frequent. Because of thetype and number of somatic symptomsthey described, 9 of the 17 patients metDSM-III criteria for the physical concom-itants of panic attack. However, none ofthe 17 patients met DSM-III criteria forpanic disorder. Although some experi-enced psychological symptoms such asalertness, wariness, and uneasiness, es-pecially during paroxysmal episodes, theydenied experiencing the severe apprehen-sion or fear bordering on terror character-istic of patients with panic disorder. Theydid not seek out others, as patients withanxiety attacks do, but preferred to restin a quiet room alone until the paroxys-mal attack ceased. Although concernedabout the potential dangers of hyperten-sion, most patients did not experience theintense fear of sudden death reported bypatients with panic disorder. After thefirst attack and reassurance that theirsymptoms were not due to a heart attack,they simply waited for subsequent attacksto end. No patient manifested anticipatoryanxiety or avoided going to work becauseof symptoms. No patient developed ago-raphobia. (A comprehensive descriptionof physical and mental symptoms in thisgroup of patients, together with an analy-sis of symptoms that discriminate signifi-cantly among patients with pheochromo-cytoma and patients with either panic or

generalized anxiety disorder, is reportedelsewhere (29).)

One pheochromocytoma-positive pa-tient was diagnosed as possible panic dis-order. Two patients met criteria for gen-eralized anxiety disorder, and two otherswere diagnosed as "possible generalizedanxiety disorder." Of the four patientswith definite or possible generalized anx-iety disorder, three were also diagnosedas having a major depressive episode; twoof these three patients were quite ill withmalignant pheochromocytoma and multi-organ involvement.

The five patients who received a diag-nosis, definite or possible, of generalizedanxiety (four patients) or panic disorder(one patient) had mean plasma E levelssignificantly higher than those of theother 12 patients (Kruskal Wallis ANOVAfor nonparametric data: 2983 ± 4493 pg/ml versus 102 ± 90 pg/ml, p < 0.02). Therewas a trend toward higher mean NE levelsin this group as well. Individual valuesare given elsewhere (29).

Pheochromocytoma-negative patients.In the pheochromocytoma-negative sam-ple of 25 patients, 2 had panic disorder, 2had generalized anxiety disorder, and 3received diagnoses of both panic disorderand generalized anxiety (at least one def-inite). In the pheochromocytoma-negativegroup, there were no significant differ-ences in mean levels of plasma or urine E



or NE between patients with and withouta DSM-III anxiety disorder diagnosis.

Correlations of Anxiety Scores andCatecholamine Levels

Norepinephrine. In the pheochromocy-toma-positive group, NE was not signifi-cantly correlated with scores on any ofthe four anxiety scales studied (SCL-90RAnxiety; SCL-90R Phobic Anxiety; Spiel-berger State; Spielberger Trait).

In contrast, in the pheochromocytoma-negative group, plasma NE was signifi-cantly correlated with scores on all fouranxiety scales. These results are shown inTable 2, upper half. When the 7 pheo-chromocytoma-negative patients with aDSM-III diagnosis were excluded from theanalysis, the correlations between plasmaNE and the anxiety scales for the remain-ing 18 pheochromocytoma-negative pa-tients remained significant, and becameeven stronger.

In the panic disorder patients, too,

plasma NE showed a significant correla-tion with scores on the SCL-90R Anxietyscale. As noted previously, the Spielber-ger Anxiety Scales were not administeredto this group. These results are also shownin Table 2.

In order to specify more precisely thenature of the relationship, we further sub-divided the 10 items comprising the SCL-90R Anxiety scale into three groups: fiveitems that describe cognitive aspects ofanxiety, two that are mixed cognitive andsomatic, and three that are primarily so-matic. These subgroups and the followingresults are shown in Table 3. In the phe-ochromocytoma-positive patients, NE wasnot significantly correlated with any ofthe 10 individual items comprising theSCL-90R Anxiety scale. In the pheochro-mocytoma-negative patients, plasma NEwas significantly correlated with four ofthe five items that are related to the cog-nitive experience of anxiety. In contrast,plasma NE was significantly correlatedwith only one of the five noncognitive ormixed items: heart racing or pounding,

TABLE 2. Correlations of SCL-90R and Spielberger Scales with Catecholamines (Pearson's Product-Moment Correlation Coefficients)

SCL-90R Anxiety ScaleSCL-90R Phobic AnxietySpielberger State AnxietySpielberger Trait Anxiety

SCL-90R Anxiety ScaleSCL-90R Phobic AnxietySpielberger State AnxietySpielberger Trait Anxiety

Pheochromocytomcpositive

Plasma

NSNSNSNS

NSNSNSNS

Urine

NSNSNSNS

NSNSNSNS

i Pheochromocytomanegative

Plasma Urine

Correlation coefficients for NE

+0.40* NS+0.55* NS+0.44* NS+0.49* NS

Correlation coefficients for ENS NSNS -0.57**NS NSNS NS

Panic

Plasma

+0.67*NSNA*NA

NSNSNANA

Urine

NSNSNANA

NSNSNANA

'p<0.05.l*p<0.01.' NA = not available.



TABLE 3. Correlations of SCL-90R Anxiety Scale Individual Items with Norepinephrine (Pearson'sProduct-Moment Correlation Coefficients)

CognitiveFearfulSuddenly scared for no rea-

sonSudden spells terrorSomething bad will happenFrightening thoughts

Mixed Cognitive/SomaticNervous, shakyTense, keyed up

SomaticTremblingRestlessnessHeart racing, pounding

Pheochromocytomapositive

Plasma

NSNS

NSNSNS

NSNS

NSNSNS

Urine

NSNS

NSNSNS

NSNS

NSNSNS

Pheochromocytomanegative

Plasma

+0.55**+0.68**

+0.46*NS+0.55**

NSNS

NSNS+0.43*

Urine

NSNS

NSNSNS

NSNS

NSNSNS

Panic dis<

Plasma

NSNS

tNS+0.63*

NSNS

+0.56*NS+0.68*

Drder

Urine

NSNS

NSNSNS

NS

NSNSNS

*p<0.05.**p<0.01.t Unable to calculate: all rated maximum.

which is consistent with its inotropic andchronotropic effects on the heart. UrinaryNE showed nonsignificant trends in thesame direction for the SCL-90R Anxietyscale and its individual items. For thepanic disorder patients there were a fewscattered positive correlations of individ-ual items with NE.

Epinephrine. In contrast to NE, E levelswere not positively correlated with scoreson any of the four Anxiety scales in anyof the three groups studied. In fact, urineE was inversely correlated with the SCL-90R Phobic Anxiety scale in the pheo-chromocytoma-negative group. These re-sults are shown in Table 2, lower half.

When the 10 items of the SCL-90R Anx-iety scale were analyzed separately,plasma E levels in the pheochromocy-toma-positive group were significantlycorrelated with three of the five somaticor mixed cognitive/somatic items (nerv-

ous, shaky r = +0.48, p < 0.05; tense,keyed up r = +0.57, p < 0.05; trembling r= +0.56, p < 0.05). In the pheochromo-cytoma-negative group, urinary E showedan inverse correlation with three of thefive items related to the cognitive expe-rience of anxiety (fearful r = -0.40, p <0.05; suddenly scared for no reason r =—0.40, p < 0.05; frightening thoughts r =-0.51, p < 0.05). When the seven pheo-chromocytoma-negative patients with aDSM-III Anxiety diagnosis were excluded,these inverse correlations between uri-nary E, the SCL-90R Phobic Anxiety scaleand cognitively experienced individualitems of the SCL-90R Anxiety scale forthe remaining 18 pheochromocytoma-negative patients remained significant.

In the panic disorder patients, no sig-nificant correlations were found for E lev-els and any of the individual items of theSCL-90R Anxiety scale.



Correlation of Somatic Symptoms andCatecholamine Levels

The SCL-90R Somatization scale in-cludes 12 items related to physical symp-toms such as faintness, weakness, nausea,tingling, dyspnea, and hot or cold spells.

Plasma E in the pheochromocytoma-positive group was positively correlatedwith scores on the somatization scale: r =+0.51, p < 0.05. Plasma E in the pheo-chromocytoma-negative group was alsopositively correlated with scores on thesomatization scale: r = +0.41, p < 0.05.When the 18 pheochromocytoma-nega-tive patients without a DSM-III anxietydiagnosis were analyzed separately, thiscorrelation remained and increased to r =+0.55. p < 0.05.

In contrast, NE in plasma or urine wasnot significantly correlated with scores onthe somatization scale in either the phe-ochromocytoma-positive or pheochromo-cytoma-negative patient group.

In the panic disorder patients, neitherE nor NE was significantly correlated withscores on the SCL-90R Somatization scale.

DISCUSSION

Despite major elevations in peripheralcatecholamine levels and considerablephysical symptoms, the great majority ofthe pheochromocytoma-positive patientswe studied did not meet DSM-III criteriafor panic or generalized anxiety disorder.None of 17 such patients we studied de-scribed the severe apprehension or fearcharacteristic of panic attacks. In fact,over 50% of our sample denied havingsignificant psychologic symptoms of anysort (29). In the pheochromocytoma-posi-tive patient group, there was no signifi-cant correlation between anxiety, as

measured by four standard scales, andplasma NE or E levels. Somatic symptoms,however, were correlated with plasma Elevels, which is consonant with ourknowledge of the peripheral effects of E.Since systemic catecholamines do notcross the blood-brain barrier in physiolog-ically significant amounts (23-25), theseresults suggest that increased peripheralcatecholamines secreted by a source au-tonomous of nervous system control andstimulation are not sufficient to elicit se-vere anxiety as defined by DSM-III crite-ria in the majority of patients, eventhough considerable physical symptomsare experienced.

There are several possible caveats tothis conclusion. First, the five pheochro-mocytoma-positive patients with definiteor possible diagnosis of anxiety disorderhad plasma E levels significantly higherthan those of the other patients. Three ofthese five patients had malignant pheo-chromocytoma with metastatic disease,which might account for their anxietysymptoms as well as the additional majordepressive disorder diagnosis found intwo of the three. Nevertheless, the possi-bility exists that extremely elevated cate-cholamine values may play some etiologicrole in the production of anxiety. Second,down-regulation of peripheral catechol-amine receptors may have occurred overtime in patients with pheochromocyto-mas, perhaps leading to decreased respon-siveness to the elevated catecholaminelevels. Against this possibility is the factthat the pheochromocytoma-positive pa-tients reported no differences in their cur-rent symptoms versus their initial ones.Despite chronic exposure to elevated cat-echolamines, they reported continuingmajor episodes of tachycardia, restless-ness, shortness of breath, and gastrointes-tinal symptoms. Third, adrenoreceptor



blocking agents may have affected thepatients' experience of anxiety, eventhough elevation of blood pressure andheart rate continued despite such medi-cations. Against this possibility is the factthat treating psychiatric patients withgeneralized anxiety disorder and panicdisorder with propranolol, a /?-adrenergicblocking medication which readily entersthe brain, has been largely unsuccessfulexcept for decreasing some of the somaticsymptoms of anxiety. In our study, pheo-chromocytoma-positive patients receiv-ing /3-adrenergic blocking medicationshad no less psychological or somaticsymptomatology than the other patientswith pheochromocytoma, as shown byStudent's t test. The pheochromocytoma-negative group provided the opportunityto examine further the possible role ofthese antihypertensive medications. Inthis group, Student's t tests revealed nosignificant differences in plasma and uri-nary E and NE levels between subgroupsof patients receiving and not receivingsuch medications. Similarly, there wereno significant differences in the anxietyscales for patients on, or not on, medica-tion. Medication did not reduce the so-matic symptoms experienced by patients;rather, the SCL-90R Somatization scale,which includes headaches, chest pain,and nausea, was higher in patients whowere taking medication (p < 0.03). Lastly,opioid peptides known to be secreted bypheochromocytomas might possibly mod-ulate and have reduced the degree ofstimulation of peripheral receptors by cat-echolamines.

In contrast to the patients with pheo-chromocytomas, in the pheochromocy-toma-negative patients, anxiety ratingswere significantly correlated with plasmaNE levels. Again, plasma E showed no

significant correlations with any of thefour anxiety scores. Moreover, plasma NEwas significantly correlated with individ-ual items of the SCL-90R Anxiety scalerelated to the cognitive experience of anx-iety, but not with items related to thesomatic symptoms of anxiety. In indi-viduals without a pheochromocytoma,plasma NE reflects sympathetic nervoussystem activity; the most direct evidencefor this observation is provided by thecorrelation of plasma NE with levels ofsympathetic activity measured electro-physiologically in muscle (34). The pat-terns of correlations we observed inthe pheochromocytoma-negative patientssuggests the hypothesis that anxiety orig-inating and experienced cognitively mayactivate and be linked to the degree ofstimulation of the sympathetic nervoussystem. Thus, NE in the periphery is, atleast in part, a marker of this central stim-ulation. There is some evidence that sup-ports the hypothesis that peripheral NEreflects increased activity of central nor-adrenergic neurons. In 159 subjects (mostof whom had neurologic disease), therewas a strong relationship between NE lev-els in blood and CSF (r = +0.78, p < 0.001),despite the effective blood-CSF barrier forNE (35). Maas et al. (36) suggest thatneuro-anatomic, physiologic, pharmaco-logic, and biochemical evidence indicatea close coupling of functional activity ofthe sympathetic nervous system and thecatecholamine systems in the centralnervous system, so that increased impulseflow in central nervous system catechol-amine systems is linked to increased im-pulse flow in the sympathetic nervoussystem.

In the pheochromocytoma-negative pa-tients, urinary E was inversely correlatedwith the cognitive manifestations of anx-



iety. The fact that the urinary ratio of NEto E also showed significant correlationswith the SCL-90R Anxiety (r = +0.50, p< 0.05) and Phobic Anxiety (r = +0.70, p< 0.01) scales further supports the finding.One speculation regarding these results isthat psychic anxiety preferentially acti-vates the noradrenergic limb of the sym-pathetic system, possibly at the "expense"of the epinephrine-secreting adrenalmedulla-activatinglimb. In humans, disso-ciated responses by the sympathetic nerv-ous system and adrenal medullary cate-cholamine release do occur in response tovarious stimuli (37). However, furtherspeculation should probably await confir-mation of our finding.

Excluding the seven patients with aDSM-III diagnosis from the analysis ofthe pheochromocytoma-negative groupstrengthened the correlations betweenplasma NE, the anxiety scales, and theindividual items of the SCL-90R Anxietyscale. This indicates that the correlationsfor the group as a whole do not result onlyfrom the contribution of patients with aclinically diagnosable anxiety disorder. Infact, the opposite was seen: there were nocorrelations between plasma NE and theanxiety scales in the subgroup with a di-agnosable anxiety disorder. On the onehand, this lack of correlation in the anxi-ety disorder patients may be artifactual.The number of subjects was small, mak-ing it difficult to achieve significance.Furthermore, one individual item of theSCL-90R Anxiety subscale: fearfulness,did show a significant correlation withplasma NE (r = +0.82, p < 0.05), and twoother cognitive items showed substantialalthough statistically nonsignificant cor-relations: suddenly scared (r = +0.65, p <0.11) and sudden spells of terror (r =+0.58, p < 0.17). On the other hand, if the

finding is not artifactual, one could spec-ulate that the patients with anxiety dis-orders differ from the remainder of thepheochromocytoma-negative group inthat they manifest a dissociation of thedegree of cognitively experienced anxietyand the magnitude of peripheral elevationof NE levels. (For example, these patientsmight hypersecrete NE so that even lowlevels of anxiety produce large NE re-sponses. Or, they might have a depletedstore of NE due to chronic release, andtherefore no ability to respond withgreater catecholamine release in the faceof greater anxiety.)

The pheochromocytoma-negative pa-tients we studied may represent a popu-lation with a specific pattern of catechol-amine response to anxiety-provokingstimuli. They were initially sent for eval-uation precisely because their paroxys-mal or sustained hypertension was asso-ciated with elevated catecholaminelevels. During our study, plasma cate-cholamines were obtained preceding ananxiety-provoking situation: a medical in-vestigation. These patients may representthat proportion of the population that re-sponds to certain conditions of stress andanxiety by elevation of NE and responsiv-ity of the vascular system. There is stillcontroversy over whether or not thereexists a subgroup of hypertensive patientswith elevated basal levels of catechol-amines and excessive sympathetic nerv-ous system responsiveness to stress (38,39). This study would tend to supportsuch a hypothesis.

In summary: 1) None of the patientswith pheochromocytoma met DSM-III cri-teria for panic disorder, while two metcriteria for generalized anxiety disorder.Since peripheral catecholamines do notcross the blood-brain barrier, the periph-



eral effects of E and NE secreted by asource autonomous of central nervoussystem control were not sufficient to elicitanxiety disorders meeting DSM-III criteriain the majority of such patients.

2) E levels were not significantly cor-related with any of the four anxiety scalesin any of the three patient groups studied.In both the pheochromocytoma-positiveand pheochromocytoma-negative pa-tients, E was significantly correlated withthe SCL-90R Somatization Scale, whichmeasures 12 physical symptoms.

3) NE levels were not significantly cor-related with any of the four anxiety scalesin patients with pheochromocytoma. Incontrast, in patients without pheochro-mocytoma and in patients with panic dis-order, plasma NE was significantly corre-lated with the anxiety scales.

4) When the 10 items of the SCL-90RAnxiety scale were categorized accordingto whether they measured a cognitive orsomatic aspect of anxiety, plasma E levelsin the pheochromocytoma-positive pa-tients were significantly correlated withthree of five somatic or mixed cognitive/

somatic items, but not with any of the fivecognitive items. In the pheochromocy-toma-positive patients, plasma NE levelswere not significantly associated with anyindividual items. In contrast, plasma NEin pheochromocytoma-negative patientswas significantly correlated with four offive items related to the cognitive expe-rience of anxiety, but only one of fivenoncognitive items.

Taken together, these observations andpatterns of correlations support the hy-pothesis that in individuals without anautonomous source of peripheral cate-cholamines, NE in the periphery (whichis primarily the result of spillover fromvascular beds in muscle) results fromsympathetic nervous system activity andprobably reflects, rather than causes, anx-iety.

This work was supported in part byUnited States Public Health Service grant5 MOl RR00042. James C. Sisson, M.D.,University of Michigan Division of Nu-clear Medicine, gave encouragement andassistance in facilitating this study.

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